1-substituted-3-pyrrolidylmethylamines



as phenylalkyl).

United States Patent This invention relates to novel amines and more particularly to l-substituted-3-pyrrolidylmethylamines and to processes for preparing the same.

Broadly, the compounds of the present invention have the formula on N i 2- \H \N i.

wherein R is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, aralkyl (such as phenylalkyl) and alkoxyaralkyl (such as alkoxypenylalkyl), and R is selected from the group consisting of hydrogen, alkyl, aryl (such as phenyl), and aralkyl (such The acid addition salts of these compounds are also contemplated as a part of this invention.

The compounds of this invention are useful as intermediates in the production of pyrrolidylquinolines and pyrrolidylquinazolines as disclosed in our copending United States application Serial No. 34,877, filed of even date herewith, now abandoned. These latter compounds have utility as anti-inflammatory agents when administered to mammals. The dosage is from about 50 to about 100 milligrams per kilogram of body weight administered from one to three times daily in the appropriate proportions. The compounds contemplated herein may be prepared by several methods, depending upon the type of product desired.

For example, the preparation of a compound of the structure Rg CHz-N wherein R' is aryl and R is as previously defined, is carried out by condensing a 1-substituted-3-pyrrolidylmethyl halide with an amine of the formula H R2I\IIH If desired, the reaction can be carried out in the presence of an acid binding agent in the form of excess amine re actant or other alkaline material, such as sodium hydride, alkali metal carbonate, or hydroxide. The reactants are preferably used in equimolar amounts. The reaction is preferably carried out under substantially anhydrous conditions. Refiuxing in a solvent is one convenient method of carrying out the process. Alternatively the condensation may be performed by heating an equimolecular amount of l-substituted-3-pyrrolidy1methyl halide and "ice R'NH at elevated temperature. The reaction proceeds as shown in the following equation:

Equation I wherein X is a halogen selected from the group of chlorine and bromine and R and R' are as defined above. In the preparation of compounds of the structure CHPN/ w \H wherein R is hydrogen, alkyl or aralkyl and R is as previously defined, the preferred process comprises reacting a 1-substituted-3-carboalkoxy-S-pyrrolidinone with ammonia or a primary amine to form a l-substituted-3- carbamoyl-S-pyrrolidinone (I) as an intermediate. This intermediate compound is then reacted with an alkali metal aluminum hydride, such as sodium or lithium aluminum hydride, preferably in a solvent under substantially anhydrous conditions. The reaction is illustrated in the following equation in which the radicals R and R" are as above defined:

The acid addition salts of the compound of this invention are conveniently prepared by the conventional techniques of the art. For example, the hydrochloride salt may be prepared by treating the free base in a solvent such as ethanol or heptane (anhydrous) with gaseous hydrogen chloride. Other salts, such as the benzoate, succinate, tartrate, mucate and the like, may be prepared by similar well known methods. The following examples will illustrate the preparation of the compounds of the present invention by the various processes disclosed above. The 1-substituted-3-pyrrolidylmethylhalides used in the examples were prepared by the method set forth in Feldkamp and Wu US. Patent No. 2,826,588. Likewise the l-substituted-3-carbalkoxy-S-pyrrolidinones may be prepared by the method disclosed in the aforesaid patent.

The following Example I will illustrate the preparation of compounds by the method of Equation I.

EXAMPLE I syrupy residue, which was scratched with a glass rod in the presence of a small amount of butauone to separate crude 1-allyl-3-carbamoyl-S-pyrrolidinone as a crystalline product, Ml. 75-80". Recrystallization from tetrahydrofuran yielded 399 g. (75%) of pure product, M.P. 78-80".

Similarly prepared were the following l-substituted 3- carbamoyl-S-pyrrolidinones: 1-methyl-, 1-ethyl-, l-isodimethoxyphenethyl)ethyl-, and l-fl-hydroxyethyland the following 1,3-disubstituted S-pyrrolidinones: l-methyl- 3-rnethylcarbamoyl-, 1-methyl-3-benzylcarbamoyl-, and 1-(2-ethylhexyl)-3-(2-ethylhexyl)carbamoyl. Their physical constants are listed in Table I below.

TABLE I.1-SUBSTITUTED3-CAR BAM OYL-5-PYRROLIDINONES (H) C-NHR' Hi It; 1 .P., Percent Formula C. yield H H 193-195 66 051mm:

CH3 H 140-141 92" CqHroNzO: CzH H 102-103 79 CTHnNzOg 0rn 121 151-152 in otnnNio, CH3 CH.-i(CHz)s- H 122-123 71 OaHisNzO:

@om- H mews as onHimioi ornorn 11 mm 71 CUHIB I Q CHBOQCHEOHT- H 137-139 82 CISHZUNiOl 1 01130 HO CHzCHr- H 118-119 72 C7HnN2 l 7 CH3 CH3- 53-55 95 C1H12Nz0:

0113-, @CHF 69 Cu raNn s CH3(CHz)3CiHCH2 CHz(CH): Cl)HCHz 1 195-200 36 021114018302 aniline as a colorless oil, B.P. 160189 (37 mm.), 11 1.5540. Pure sample was obtained by redistillation in vacuo, B.P. 113115 (0.08 m1n.)n 1.5540.

The following Examples II through XIV were prepared by the method of Equation II.

EXAMPLES II-XIV 1Substituted-3-Pyrr0lidylmethylamines EXAMPLE II 1 A llyl-S- (An-tin omethyl Pyrroli d1 ne A. 1-allyl-3-carbam0yZ-S-pyrrolidinone (intermediate). A solution of allylamine (186.7 g., 3.27 moles), dimethyl itaconate (517.0 g., 3.27 moles) and 1 liter of anhydrous methanol was prepared and allowed to stand at room temperature for three days to form 1-allyl-3-carbomethoxy-5- pyrrolidinone. The solution containing the 1-ally1-3-carbomethoxy-5-pyrrolidinone was then cooled in an ice bath and anhydrous ammonia was added until. a large excess was present. After standing at room temperature for three days, the reaction mixture was heated to boiling to drive off most of the excess ammonia, concentrated to a B. 1-allyl-3-(Aminoethyl)Pyrr0Zidine.-To a slurry of lithium aluminum hydride (27 g., 0.71 mole) in 260 ml. of tetrahydrofuran was added dropwise with stirring a suspension of 1-allyl-3-carbamoyl-S-pyrrolidinone (60 g., 0.36 mole) in 200 ml. of tetrahydrofuran at such a rate that gentle refluxing was maintained. The addition took approximately one hour. The mixture was then refluxed and stirred for three and one-half hours. During this period, additional tetrahydrofuran ml.) was added in order to keep the mixture fluid.

The reaction mixture was cooled in an ice bath, and

distillate, B.P. ll8124 (20 mm.). Redistillation yielded 25.1 g. (50%) of a pure product, Bl. 100 (20 mm); n 1.4853.

A number of additional 3-pyrrolidylrnethylamines were prepared as Examples III through XIV by essentially the same procedure. Their identity and physical constants are indicated in Table II.

TABLE II.1-SUBSTITUTE D-3-PYRR OLIDYLMETHYLAMINE S Example R1 R2" B.P., m 0.) Percent Formula 0. (mm) yield TTT H H 78 (13) 1. 4864 (24) 50 C5H12Na IV 0113-" H 166-167 (760) 1. 4648 (24) 60 CeHuNz V C 115-- H 8990 (20) 1. 4613 (20) 08 C 7H1GN2 VI /CH- H 106-108 (38) 1. 4603 (25) 42 CaHrsNz VII CHa(CH2) 3 H 110-114 (20) 1. 4653 (20) 51 CaHzuNz VIII Cl1z H 126 (0. 3) 1. 5400 (20) 71 CHHIBNH IX @omom- H 90-92 (0. 0c) 1. 5349 24. 5) 66 CuHzoNz X CH3O'OH2OH;4 H 141-144 (0. 07) 1. 5420 (25) 70 C H24Na0z XI HO CHgCI-l'o H 86 (0. 006) 1. 5050 56 otHinNgO XII CH C 113-. 54(13) 1. 4516 (24) 67 C 7H1BN2 XIII CH3 CH2-- 169-172(24) 1. 5237 (25) O1SH20N2 XIV csnn- (2 ethyl hexyl) CiHnT) (2-ethyl 182-194 (5) 1. 4614(26) 78 CziHtiNz exy As previously indicated, the compounds of this inven tion are suitable for the preparation of certain 4-substituted quinolines and quinazolines as disclosed in our copending application Serial No. 34,877. In accordance with one embodiment of the disclosure in that application, a 1-substituted-3-pyrrolidylmethylamine of this invention is reacted with a 4-chloroquinazoline or a 4-mercaptoquinazoline to produce a 4(l-substituted-S-pyrrolidylmethylamino)quinazoline. Examples of the procedure are as follows:

A. From 4-clzloroqzzinazoline.-To a solution of 8 g. (0.049 mole) of 4-chloroquinazoline in 200 ml. of anhydrous ether Was added, in one portion, 11.1 g. (0.097 mole) of 1-methyl-3-pyrrolidylmethylamine as a solution in 60 ml. of anhydrous ether. The resulting solution became cloudy immediately With precipitated hydrochloride. After standing at room temperature for twenty-four hours, the ether was removed on the steam bath and the residue dissolved in 150 ml. of Water. The Water solution Was made alkaline (pH 12-13) with 20% sodium hydroxide and the oily mixture extracted three times With chloroform. The combined chloroform extracts were washed once with water, once with saturated sodium chloride solution and then dried over magnesium sulfate. After removing the chloroform the residual oil was dissolved in 50 ml. of hot acetonitrile, the solution treated with Norite brand activated charcoal, cooled, and seeded to yield 7.1 g., 61%, M.P. 109.5-111".

B. From 4-mercaptoquinazoline.4-mercaptoquinazoline, 23.1 g. (0.143 mole) prepared as disclosed in Leonard and Curtin, J. Org. Chem, 11, 349 (1946), and 1- methyl-3-pyrrolidylmethylamine, 24.4 g. (0.214 mole), were placed in a 100-1111. round bottom flask equipped funnel and Washed once with ice cold 10% sodium hydroxide and then With water. After drying over magnesium sulfate, the chloroform was removed in vacuo and the residual oil diluted slightly With butanone and'chilled to give a solid mass. Seed crystals were removed and the material (treated with activated charcoal) recrystallized twice from acetonitrile to yield 22.7 g. (66%), M.P. 11 1-1 12 While a particular embodiment of this invention is shown above, it will be understood, of course, that the invention is not to be limited thereto, since many modifications may be made, and it is contemplated, therefore, by the appended claims, to cover any such modifications as fall Within the true spirit and scope of this invention.

We claim:

1. l-lower alkyl-3-(anilinomethyl)pyrrolidine.

2. l-methyl-3-(anilinomethyl)pyrrolidine.

3. l-(hydroxyalkyl)-3(aminomethyl)pyrrolidine.

References Cited in the tile of this patent UNITED STATES PATENTS 2,651,639 Angier Sept. 8, 1953 3,031,452 Shen et al. Apr. 24, 1962 FOREIGN PATENTS 197,817 Austria May 27, 1958 OTHER REFERENCES Reitsema: J. American Chem. Soc., vol. 71, pages 2041-2043 (1949).

Bergmann: The Chemistry of Acetylene and Related Compounds, p. (1948).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 133,082 May 12, 1964 Yao Hua Wu et a1.

It is hereby certified that error appears in the above numberedpatent requiring correction and that the said Letters Patentshould readas corrected below.

Column 3, line 3, for "pyrolidine" in italics read pyrrolidine in italics; line 55 for read n line 57 for "n read n column 1 line D "D25 D 74, for "(aminoethyl)" read (aminomethyl) column S line 26 20 2 for "LID read n --a Signed and sealed this 8th day of September 1964.,

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Altesting Officer Commissioner of Patents 

3. 1-(HYDROXYALKYL)-3-(AMINOMETHYL)PYRROLIDINE. 